Process for preparing esters of 2-hydroxy-3-(3-indolyl) alkanoic acids



United States Patent 3,320,282 PROCESS FOR PREPARING ESTERS 0F Z-HY-DRQXY-S-(3-INDOLYL)ALKANOIC ACIDS Manfred Schach von Wittenau and BillieKenneth Koe, Gales Ferry, Conn, assignors to Chas. Pfizer & Co., Inc.,New York, N.Y., a corporation of Delaware No Drawing. Originalapplication Oct. 29, 1962, Ser. No. 233,911. Divided and thisapplication Feb. 24, 1965, Ser. No. 444,481

4 Claims. (Cl. 260-32613) This application is a division of ourapplication Ser. No. 233,911, filed Oct. 29, 1962, said latterapplication being a continuation-in-part of our application Ser. No.136,173, filed Sept. 6, 1961, both now abandoned.

This invention is concerned with new and useful antimicrobial agents andwith the methods for their synthesis. Each of these new and novelproducts is useful in combating pathogenic microorganisms, includingGram-positive and Gramnegative bacteria. They are also useful asdisinfecting agents against pathogenic microorganisms, in separatingmixtures of microorganisms and in classifying microorganisms fordiagnostic research purposes.

The compounds of this invention comprise:

R is selected from the group consisting of hydrogen, chloro, fiuoro,nitro, amino, alkyl of one to four carbon atoms and alkoxy of one tofour carbon atoms;

R is selected from the group consisting of chloro, fluor-o, nitro,amino, alkyl of one to four carbon atoms and alkoxy of one to fourcarbon atoms;

R is alkyl of one to three carbon atoms;

R, is selected from the group consisting of hydrogen, phenyl, anisyl,toluidyl and alkyl of two to four carbon atoms; and

R is selected from the group consisting of hydrogen, phenyl, anisyl,toluidyl and alkyl of one to four carbon atoms;

provided that when R is methyl, R is other than alkyl and R is otherthan methyl.

Among the typical member compounds of this invention are such novelcompounds as:

1-[ 3- (4,7-dichloro)indolyl] -1-[5- (2-ethylimino-4-keto) oxazolidinyl]ethane;

l-[3(5-amino) indolyl]-1-[5-(2-(is0)-propylimino-4- keto)oxazolidiny1]propane and l- 3- (4-methoxy) indolyl] -1- [5- (2-imino-4-ketooxazolidinylethane.

A general preparative method which is applicable to the synthesis ofthese compounds involves the reaction of a substituted guanidine with ahydroxy indole acid ester. Another method of synthesis involve thereaction of 3- acyl indoles with iso-hydantoins and subsequent reductionof the resulting product to yield the desired compounds of the presentinvention. Still another method of preparing these compounds is thecondensation of a hydroxy indole acid ester with aZ-substituted-Z-isothiopseudo-urea to yield the desired product.

The preferred synthetic route, involves the reaction of a hydroxy indoleacid ester with a substituted guanidine, as represented by the followingequations:

wherein R R R and R are defined as aforementioned; R is lower alkylcontaining from one to three carbon atoms and R is selected from thegroup consisting of hydrogen, chloro, fluoro, nitro, amino, alkyl of oneto four carbon atoms and al-kyl of one to four carbon atoms. Thisreaction may also be employed to produce compounds wherein the3-position of the oxazolidine ring is substituted.

This reaction is preferably conducted in the presence of an inert polarorganic solvent, such as lower oxygenated aliphatic compounds. Typicalorganic solvents which may be employed are ethers, esters, ketones andalcohols. In particular, lower aliphatic alcohols containing from one tofour carbon atoms are the solvents of choice. It is desirable that thissolvent be present in suflicient amounts to dissolve each of thestarting materials. The reactants are preferably present insubstantially equimolar quantities, although the reaction may beconducted in the presence of higher quantities of the appropriateguanidine.

In general, the reaction is preferably carried out within thetemperature range of about 20 C. to about reflux temperatures for aperiod of about one-half to forty-eight hours. Recovery of the desiredproduct is most conveniently accomplished by evaporation of the organicsolvent. Alternatively, the reaction product may be recovered byextraction with an immiscible solvent which subsequently is removed byevaporation. Still another procedure for the separation of the productsof this invention is by the use of column chromatography.

The starting substituted guanidines necessary for the process of thisinvention can either be commercially obtained or they can be prepared bythe reaction of a cyanamide with a primary amine. This procedure wasdescribed by H. King and I. 'Ionkin in the Journal of the ChemicalSociety, 1946', page 1063. Many of the commercially available guanidinesare obtained as the inorganic acid salts. The guanidine salts soobtained are easily converted to the corresponding base employed in thisreaction by any number of standard and convenient procedures. Forexample, methyl guanidine may be prepared by dissolving the commerciallyavailable methyl guanidine sulfate in an anhydrous, sodium alcoholate.When the reaction is complete, the solution is filtered to remove theinsoluble sodium sulfate and the filtrate is concentrated. This solutioncontains methyl guanidine as the free base. It is even possible toemploy the guanidine acid salts, as such, by adding this compound andthe hydroxy indole acid ester to the alcoholic solution of a sodiumalkoxylate; in this case, the guanidine base is formed in situ and thenreacts with the hydroxy indole acid ester.

sented by the following equations:

R1 H H +RC-COOB a wherein R, R R and R are defined as aforementioned.

This reaction may be conducted in the presence of an inert polar organicsolvent, such as benzene, chloroform and lower oxygenated aliphaticcompounds. Normally, it is preferable that this solvent is present insufficient amounts to dissolve each of the starting materials which arepreferably present in substantially equimolar quantities.

This reaction when conducted in the presence of the aforesaid solventmay be carried out within the temperature range of about 50 C. to about160 C. with a preferred temperature range from about 100 C. to about 140C. The reaction time varies with the temperature. Generally, the higherthe reaction temperature the shorter the reaction time. Reaction timesvary from about onehalf to forty-eight hours. This reaction may be acidcatalyzed. The catalysts which may be employed are phenol,2,6-dimethylphenol and inorganic acids including Lewis acid such asaluminum chloride, aluminum bromide, tin chloride, etc. When phenol isemployed as the catalyst, the reaction can also be conducted by admixingthe reactants when phenol at temperatures as high as 265 C. for aboutone to three hours, without the use of the aforesaid solvents.

The aforementioned reaction may also be conducted by simple admixing anindole or a substituted indole with an alkyl 2,3-epoxyalkylate in asealed container and heating said container until the reaction iscomplete. This reaction may be carried out at a temperature of about 180C. to about 275 C. with a, preferred temperature range from about 240 C.to about 265 C. The reaction time varies with the temperature from oneto ten hours.

Another preferred method of synthesizing the hydroxy indole acid estersof this invention is an adaptation of the .method employed byGortatowski and Armstrong, in the Journal of Organic Chemistry, volume22, page 1217 (1957), for the synthesis of indole lactic acid.Generally, this method involves the reaction of a substituted indolewith an aldehyde and isopropyla-mine to produce the corresponding3-(isopropylaminoalkylidine)-substituted in-' dole. Reacting thiscompound with diethylacetoxymalonate in the presence of metallic sodiumor sodium methoxide as a catalyst, there is obtained the diethyl [3(substituted) indolyl alkylidine]acetoxymalonate. When this product ishydrolyzed and subsequently decarboxylated, the resulting product isa-hydroxy-fi-alkylflit-(substituted) indoly1]propionic acid which isreacted with a diazoalkane to produce the desired starting ester. Thelength of the R alkyl moiety in the hydroxy indole acid esters will bedetermined by the aldehyde employed in the first reaction of theheretofore discussed reaction sequence. For example, when it is desiredthat R be a propyl group, the aldehyde employed is butylaldehyde.

Still another procedure for the synthesis of the hydroxy indole acidesters employed in the formation of the compounds of this inventioninvolves the reaction of a substituted indolyl magnesium iodide with analkionyl chloride by the procedure described in Beilstein, volume 21, I,302. The 3-alkionyl(substituted)indole obtained in this manner is thenheated with glycolylurea in the presence of piperidine or aceticanhydride and sodium acetate to obtain the corresponding hydantoincompound. Hydrolyzing this compound by the procedure described inChemical Reviews 38, 526, and, thereafter, reacting this product withsodium borohydride, the corresponding a-hydroxy-B[3-(substituted)-indolyl]alkanoic acid is obtained. The desiredstarting ester is formed by reacting the aforementioned compound with anappropriate diazoalkane.

When it is desired to form the compounds of this invention in which theR R are hydrogen and R is methyl, the starting hydroxy indole acid estermay be obtained by the degradation of an antibiotic which is obtained bythe fermentation of Streptomyces albus. This antibiotic was isolated byMarch et al. and reported in Antibiotics and Chemotherapy, volume X, No.5, page 315. Its physical and chemical properties have been described byK. Rao in Antibiotics and Chemotherapy, volume X, No. 5, page 312. Whenthis antibiotic is hydrolyzed by alkali, there is obtained the desiredZ-hydroxy-3-(3-indolyl)butyric acid which may be esterified asheretofore described. More particularly, this hydrolysis is conducted byrefluxing 1 gram of the antibiotic in a mixture of 40 milliliters of a10% sodium hydroxide solution and 10 milliliters of a 5% bariumhydroxide solution. The basic hydrolysis products are distilled off by astream of nitrogen as they are formed during the refluxing period. Whenthe hydrolysis is complete, the reaction mixture is filtered to removethe precipitated barium carbonate and the filtrate acidified with 1 Nhydrochloric acid to a pH of 2. This solution is extracted with threemilliliter portions of ether and when the ether is evaporated theresidue is 2-hydroxy-3-(3-indolyl) butyric acid. After severalrecrystallizations from an ether-chloroform mixture, this acid meltsbetween 177 C. and is obtained in approximately a 46% yield.Subsequently, an ethanolic solution of this acid is reacted with anexcess of diazomethane and the resulting product is the desired hydroxyindole acid ester which is employed in the synthesis of some of thecompounds of this invention.

The antibiotic compounds of this invention have activity against avariety of microorganisms, including both Gram-positive andGram-negative bacteria which are resistant to many of the commonlyemployed antibiotics, for example, when compounds of this invention areadministered to mice which have been infected with an otherwise lethaldose of tetracycline resistant strains of Staphylococcus aureus, theyafiorded life-saving protection to the infected mice. Another advantageof these antibiotics is that they are remarkably non-toxic when they areadministered to mice by the oral, intraperitoneal and subcutaneousroutes.

In connection with the use of the previously described compounds of thisinvention as antimicrobial agents, they may be administered alone or,preferably in combination with a pharmaceutically acceptable carrier,and as such can be given in single or multiple doses. More particularly,the antimicrobial compounds of this invention may be administered insuitable dosage forms providing a dosage unit of the active ingredientin an amount that is adjusted to the particular needs of the individual.When large doses of these antimicrobial agents are to be used, it ispreferable to administer two or more doses at various time intervals, asselected by the attending physician.

These antimicrobial compounds may be administered in a variety of dosageformulations, i.e., they may be combined with various pharmaceuticallyacceptable inert carriers in the form of capsules, tablets, lozenges,troches,

.are suitable for the manufacture of hard candies, suspensions,solutions, elixirs, parenteral solutions and suspensions, ointments,soaps and powders. The carriers employed include, solid diluents,ointment bases, aqueous vehicles, non-toxic organic solvents and thelike. In general, the compounds of this invention are present in variousdosage forms at concentration levels ranging from about 0.5% to about90% by weight of the total composition, i.e., in amounts which aresufiicient to provide the desired dosage.

For purposes of oral administration, tablets containing variousexcipients, such as sodium citrate, calcium carbonate and dicalciumphosphate may be employed along with various disintegrants such asalginic acid and certain complex silicates, together with binding agentssuch as polyvinylpyrrolidone, gelatin, and acacia; in addition,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tableting purposes. Solid compositions ofa similar type may also be employed as fillers in soft elastic andhard-shelled gelatin capsules, preferred materials in this connectionwould also include polyethylene glycol and glycerin as they not only maybe used in this particular type of pharmaceutical dosage form asdiluents, but also as plasticizing agents serving to protect the capsuleagainst any leakage that might possibly occur due to denaturation of thegelatin protein. When aqueous suspensions and elixirs are desired fororal administration, the antimicrobial ingredient may be combined withvarious sweetening and flavoring agents, coloring matter or dyes and, ifso desired, emulsifying and suspending agents, together with suchdiluents as water, ethanol, propylene glycol, glycerin and variouscombinations thereof.

Solutions or suspensions of these antimicrobial compounds inpyrogen-free, sterile distilled water containing a preservative such asbutyl paraben, propyl paraben, chlorobutanol, phenol and the like may beutilized for parenteral administration by intramuscular or intravenousinjection. Similar aqueous preparations, where the concentration ofactive ingredients are normally lower, may be employed as opthalmicsolutions.

For use as a dusting powder, the active ingredients of this inventionare mixed with any of a number of extending'agents either organic orinorganic in nature which pulverulent preparations. These include, forexample, tricalcium phosphate, calcium carbonate, kaolin, talcum, boricacid and others. These mixtures may be used in the dry form or, by theaddition of wetting agents, the dry powder can be rendered wettable bywater so as to be suitable as a topical suspension.

For special purposes, the agents of this invention can be worked intothe form of a paste or an ointment by the use of such semi-solidextending agents as soap petroleum jelly, carbowax, glycerin or lanolinwith or without the aid of solubility promoters or dispersing agents.

In all these various formulations, the active antimicrobial agents canbe one or a plurality of the compounds of this invention. The compoundsmay also be advantageously employed in combination with otherantimicrobial agents or in combination with other pharmaceuticalcompounds. There may be mentioned by way of example, acetylsalicylicacid, salicylamide, antihistamines, and ascorbic acid. In this manner,it is possible to obtain mixtures which will combat the microorganismsand produce an overall well-being in the patient.

The following examples are given solely for the purpose of illustrationonly and are not be construed as limitations of this invention manyvariations of which are possible without departing from the spirit orscope thereof.

Example I To 40 milliliters of absolute ethanol in which there aredissolved 225 mg. of metallic sodium, there are added 1.22 g. of methylguanidine sulfate and the mixture is stirred for 30 minutes. Afterfiltration to remove the insoluble sodium sulfate, 850 mg. ofmethyl-2-hydr-oxy-3- (3-indolyl)butyrate are added to the filtrate andthe mixture is held at room temperature for 48 hours. When the ethanolicsolvent is removed under vacuum, the remaining residue is a mixture ofl-(3-indolyl)-1-[5-(2 methylimino-4-keto)oxazolidinyl]-ethane and1-(3-indolyl)-1- [5-epi 2-methylimino-4-keto oxazolidinyl] ethane whichare separated by paper chromatography.

Example 11 An absolute propanol solution containing 0.20 M of phenylguanidine and 0.10 M of ethyl-2-hydr-oxy-3-(3-indolyl)valerate isrefluxed for 1 hour. Thereafter, the propanol is removed under reducedpressure and the residue crystallized from ethanol. The crystallineproduct is a mixture of 1-(3-indolyl)-1-[5-(2-phenylimino-4-keto)oxazolidinyl] propane and1-(3-indolyl)-1-[5-epi(2-phenylimino-4-keto)oxazolidinyl] propane whichare separated by paper chromatography.

Example III To milliliters of absolute methanol containing 1.84 g. ofpropyl guanidine, there are added 2.6 g. of propyl- 2'hydroxy-3-[3-(5,6-dimethoxy)-indolyl]butyrate. The resulting mixture isheld for 20 hours at 50 C. When the methanol is removed by evaporation,the remaining solid is a mixture of 1-[3-(5,6-dimethoxy)indolyl]-1-{5[2-(n)-propylimino-4-keto]-oxazolidinyl}ethane and l- [3 (5,6dimethoxy)indolylJ-l-{S-epi[2-(n)-propylimino-4-keto]-oxazolidinyl}ethanewhich are separated by fractional crystallization.

Example IV With stirring 50 ml. of absolute butanol containing 1.5 g. ofanisyl guanidine are added to 50 ml. of an absolute butanol solutioncontaining 1.0 g. of methyl-2-hydroxy-3-[3-(4fluoro)indolyl]-4-methyl-valerate. The resulting mixture agitatedfor 10 hours at 65 C. Subsequently, the but'anol is removed underreduced pressure and the residue crystallized from absolute ethanol. Thecrystalline material obtained is a mixture 1-[3-(4-fluoro)inclolyl] 1 [5(2-anisylimino-4-keto)oxazolidinyl]-Z-methyl propane and1-[3-(4-fluoro)indolyl]-1-[5(2-anisylimino-4-keto)oxazolidinyl]-Z-methyl propane which are separatedby fractional crystallization.

Example V The procedure described in Example II is repeated using otherstarting materials and reagents in place of those specificallymentioned. For the sake of convenience and in order to avoid unnecessaryrepetition of experimental details other compounds which can be preparedin this manner are listed below:

(1) 1 [3 (6 methyl)indolyl] 1 [5 (2 imino- 4-keto) oxazolidinyl] butane(1) 1 [3 (7 nitro)indolyl] 1 [5 (2 ethylirnino- 4-keto) oxazolidinyl]ethane (3) 1 [3 (4,7 -dichloro)indolyl] 1 [5 (2 toluidylimino-4-keto)oxazolidinyl] ethane (4) 1- [3 (5 amino)indolyl] -1-{5 [2 (iso)propylimino-4-keto] oxazolidinyl} propane (5) 1 [3 (4 chloro)indolyl] 1[5 (2 methylimino-4-keto oxazolidinyl] ethane (6) 1{3 [7(iso)-propyl]indolyl} 1 [5 (2 phenylimino-4-keto) oxazolidinyl] ethane(7) 1- [3 (5 butyl)indolyl] -1-[5 (2 butyl 4 keto) oxazolidinyl] propaneExample VI With stirring, 28.2 g. of phenol and 70.2 g. of indole aredissolved in 39.0 g. of ethyl-2 3-epoxy butyrate. The resulting solutionis heated at C. for 18 hours and, thereafter, diluted with 1000 ml. ofdiethyl ether. This mixture is extracted with four 50 ml. portions of achilled 0.5 N sodium hydroxide solution. The diethyl ether phase isdried over sodium sulfate and evaporated. The residue is dissolved in 75ml. of ethyl acetate and chromatographed on an aluminum oxide column.The column is developed by the addition of 6000 ml. ethyl acetate,followed by elutions with 4000 ml. of a 1% ethanol-99% ethyl acetatemixture. The first 6000 ml. eluate portion is discarded and the last4000 ml. portion is distilled under a 0.5 mm. vacuum.

The product had a boiling point of 170-180 C. This material wasrechromatographed by the procedure described above and the productobtained was ethyl-Zhydroxy-3-(3-indolyl)butyrate.

Example VII A mixture containing 13 g. of ethyl-2,3-epoxy butyrate, 11.7g. of indole and 9 g. of toluene sulfonic acid were heated at 140 C. for/2 hour. The residue is dissolved in 100 ml. of ethyl alcohol to whichthere is added 250 ml. of a 2 N sodium hydroxide solution. This mixturewas refluxed for one hour during which 500 ml. of water were graduallyadded to the mixture. Thereafter, the reaction mixture was extractedwith three 500 ml. portions of ethyl acetate. The combined ethyl acetateportions are dried over sodium sulfate and evaporated under vacuum. The5.3 g. of residue was shown to contain by paper chromatographyethyl-2-hydroxy-3-(3-indoyl) butyrate. I

Example VIII A mixture of 12.6 g. of 4,7-dichloro indole, 13 g. oftrifluoro acetic acid and 13 g. of ethyl-2,3-epoxy propionate isrefluxed for 30 minutes. Thereafter, the mixture was admixed with 50 ml.of ethyl alcohol and 250 ml. of a 2 N sodium hydroxide solution and theresulting mixture is refluxed for an additional hour. Thereafter, thereaction mixture is extracted with three 500 ml. portions of ethylacetate. The aqueous phase is acidified to a pH of 2 by the addition ofconcentrated hydrochloric acid and is again extracted with three 500 ml.portions of ethyl acetate. The combined ethyl acetate portions are driedover sodium sulfate and subsequently evaporated under vacuum. Theresulting residue was shown to consist mainly of 4.86 g. ofethyl-2-hydroxy-3-[3-(4,7- dichloro indolyl] propionate.

Example IX To 150 ml. of benzene there is added 12.7 g. of 5-1116- thoxyindole, 13 g. of methyl-2,3-epoxy butyrate and 9 g. of aluminumchloride. This mixture is refluxed for one hour and the residue isadmixed with 100 ml. of ethyl alcohol 250 ml. of a 2 N sodiumhydroxidesolution and 250 ml. of water. The benzene is removed by evaporationunder reduced pressure and the residue is refluxed for one hour.Subsequently, the mixture is extracted three times with 500 ml. portionsof ethyl acetate. The aqueous phase is acidified to a pH of 2 by theaddition with stirring of concentrated hydrochloric acid. This acidifiedsolution is again extracted with three 500 ml.

portions of ethyl acetate. The combined ethyl acetate portions are driedover sodium sulfate and evaporated under vacuum. The residue remainingweighed 2.7 g. and was shown by paper chromatography to consist mainlyof methyl-2-hydroxy-3-[3(5-methoxy)indolyl]butyrate.

The procedure described above was repeated employing zinc chloride asthe catalyst.

Example X The procedure described in Example V1 is repeated using otherstarting materials and reagents in place of those specificallymentioned. For the sake of convenience, and in order to avoidunnecessary repetition of experimental detail, other compounds which canbe prepared in this manner are listed below:

(1 methyl-2-hydroxy-3- [3- 5 -methoxy) indolyl1butyrate (2)methyl-2-hydroxy-3 [3- 5,6-dimethoxy indolyl] butyrate (3)ethyl-2-hydroxy-3 [3- 5 -chloro) indolyl) ]butyrate (4) ethyl-2-hydroxy-3 (3-indolyl butyrate (5 propyl-2-hydroxy-3 (3 -indolyl)butyrate (6) ethyl-2-hydroxy-3 (3 -indolyl -4-methyl valerate (7)methyl-2-hydroxy-3 [3-( S-chloro) indolyl] -4-methyl valerate (8)ethyl-2-hydroxy-3 [3- 7-fluoro indolylJbutyrate (9) methyl-2-hydroxy-3[3- (-6-amino indolyl] butyrate 10) propyl-Q-hydroxy-3 [3-( S-ethyl)indolyl] butyrate Example XI The procedure described in Example 11 isrepeated using as starting materials the compounds listed in Example Xand the appropriate guanidines. The compounds prepared in this mannerare listed below:

(1) 1-[3-(5-methoxy)indolyl]-1-[5-(2-imino-4-keto)- oxazolidinyl] ethane(2) 1-[3-(5,6-dimethoxy)indolyl]-1-[5-(2-imino-4- keto) oxazolidinyl]ethane (3) 1-[3-(5-chloro)indolyl]-l-[5-(2-irnino-4-keto)- oxazolidinyl]ethane (4) 1-(3-ind0lyl) 1-[5-(2-anisylimino-4-keto)oxazolidinyl] ethane(5) l-(3-indolyl)-l-[5-(2-imino-4-keto)oxazolidinyl]- ethane (6) 1-(3-indolyl) -1- [5-(2-imino-4keto) oxazolidinyl] 2-methyl propane (7)1-[3-(5-chloro)indolyl]-l-[5-(2-imino-4-keto)- oxazolidinyl1-2-methylpropane (8) 1-[3-(7-fluoro)indolyl]-l-[5-(2-imino-4-keto)-oxazolidinyl]ethane (9) 1-[3-(6-amino)indolyl]-l-[5- (2-imino-4-keto)oxazolidiny1]ethane (10) l-[3-(5-ethyl) indolyl] -1-[5-(2-imino-4-keto)-oxazolidinyl]ethane What is claimed is: 1. A process for the productionof a compound of the formula:

Il a CH-CHCOOR wherein R and R are as previously defined; with acompound of the formula:

wherein R and R are as previously defined.

9 10 2. The process of claim I conducted in the presence OTHERREFERENCES of an acid catalyst. 4

3. The process of claim 2 wherein the acid catalyst is 5 3? 351'Blochem' Jour" VOL 6 September pheml- Oda: Chemical Abstracts, vol. 48,1954, p. 1935s.

4. The process of 012mm 2 wherein the acid catalyst is 5 Rodd Ed"Chemistry of Carbon Compounds VOL Iv a Lewls part A, Elsevier PublishingCo., New York, 1957, p. 92.

References Cited by the Examiner AL X MAZEL, Primary Examiner.

UNITED STATES PATENTS HENRY R. IILES, Examiner.

3,076,814 2/19 3 Speeter et a1, 260--319 10 MARY OBRIEN, AssistantExaminer.

1. A PROCESS FOR THE PRODUCTION OF A COMPOUND OF THE FORMULA:3-(R-OOC-CH(-OH)-CH(-R3),R1,R6-INDOLE WHEREIN